Human CD26, a Type II membrane glycoprotein with intrinsic dipeptidylpeptidase IV (DPPIV) activity and ability to bind Adenosine Deaminase Type I (ADA-1), is expressed on epithelial cells constitutively, but on T lymphocytes its expression is regulated.
Initially identified as a 105 kDa T cell activation antigen defined by the monoclonal antibody Ta1 (1), the CD26 antigen was subsequently shown to delineate the T cell subset responding to recall antigens (2, 3). Although the antigen is expressed in the liver, kidney and intestine (4), only in the T cell are the levels of membrane CD26 under tight cellular regulation with expression upregulated upon cell activation. CD26 has been shown to have dipeptidylpeptidase IV activity (DPPIV, EC 3.4.14.5) in its extracellular domain (5, 6) and the costimulatory potential appears to be partially dependent upon this enzyme activity (7) which can cleave amino terminal dipeptides with proline, and less effectively, alanine in the penultimate position (8). Although a substrate of relevance to T cell activation has not yet been identified, other substrates, including the neuropeptide substance P, may be processed in vivo by DPPIV/CD26 (9).
CD26 not only marks the activated state but is itself involved in the signal transducing process: crosslinking of CD3 and CD26 results in enhanced T cell activation in the absence of antigen-presenting cells (10). It is unlikely that CD26 is directly involved in transducing the activation signal across the T cell membrane since it has only a very short cytoplasmic region of 6 amino acids (11). The protein tyrosine phosphatase, CD45RO, has been shown to associate with CD26 and may provide a putative mechanism for the costimulation (12). Other associations include the strong binding of Adenosine Deaminase Type I (ADA-1) to CD26 (13). This may be of particular importance since ADA activity helps regulate the early stages of signal transduction in T lymphocytes (14). That the costimulatory potential of CD26 occurs extracellularly has been confirmed by showing that a soluble recombinant CD26 (rsCD26) representing the extracellular domain can enhance the T cell-mediated reaction to recall antigens (15). Reinforcing the proposal that soluble CD26 is costimulating, it has been found that in the absence of recall antigen, the rsCD26 has no effect upon the proliferative response. A natural form of soluble DPPIV/CD26 can be identified in normal human serum. The levels of this naturally-occurring soluble DPPIV influenced the level of reactivity of T cells to recall antigens (15).